Introduction: The prognostic differences between neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) remain unclear. Methods: This study aimed to compare the prognostic outcomes of NEC and MiNEN by analyzing the clinicopathological features of these diseases and exploring factors affecting progression after radical surgery. Additionally, we employed whole-exome sequencing to investigate the molecular mechanisms influencing the prognosis of both conditions. Results: Among the 252 patients followed, 163 underwent surgical treatment. The median time to tumor progression was 16 months (range: 9–56 months). Tumor pathology type (p = 0.007), lymph node metastasis (p < 0.0001), and distant metastasis (p < 0.0001) were identified as independent factors affecting disease progression in NEC and MiNEN patients. MiNEN patients without lymph node or distant metastasis generally had a better prognosis. First-line chemotherapy regimens did not show a significant impact on disease progression (p = 0.160, median progression-free survival [mPFS]: 36 vs. 13 vs. 23 vs. 15 months). However, the etoposide plus cisplatin (EP) regimen has shown good efficacy in gastric neuroendocrine neoplasms (NENs) (p = 0.048, mPFS: 45 vs. 12 vs. 32 vs. 16 months), especially in gastric MiNENs (p = 0.022, mPFS: Undefined vs. 11 vs. 52 vs. 37 months). Further investigation into the genetic mutation differences between NECs and MiNENs revealed that among previously sequenced data, rectal NECs commonly exhibited mutations in MUC16, SPTA1, ATM, PDGFB, NF1, FAT4, AR, APC, ANTXR2, and ADGRA2. In contrast, rectal MiNENs showed common mutations in NOTCH2, ZNRF3, CARD11, TP53, OBSCN, FPR1, APC, ANGPT2, ARID1A, and AR. Mutations in ANGPT2 and OBSCN were present in two rectal MiNEN cases, while NF1 and PDGFB mutations were found in two rectal NEC cases but not in MiNENs. The JAK-STAT signaling pathway appears to be specific to rectal NECs and may be involved in tumor progression. Conclusion: EP regimen remains the most effective chemotherapy option for neuroendocrine tumor patients. There were prognostic differences between NECs and MiNENs, as well as differences in genetic mutations and signaling pathways. This study provided new insights into the prognosis assessment and treatment strategies for NENs, particularly highlighting the importance of personalized treatments and the development of novel targeted therapies.

1.
Nagtegaal
ID
,
Odze
RD
,
Klimstra
D
,
Paradis
V
,
Rugge
M
,
Schirmacher
P
, et al
.
WHO classification of tumours: digestive system tumours
.
Histopathology
.
2020
;
76
(
2
):
182
8
.
2.
Chai
SM
,
Brown
IS
,
Kumarasinghe
MP
.
Gastroenteropancreatic neuroendocrine neoplasms: selected pathology review and molecular updates
.
Histopathology
.
2018
;
72
(
1
):
153
67
.
3.
Singhi
AD
,
Klimstra
DS
.
Well-differentiated pancreatic neuroendocrine tumours (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs): concepts, issues and a practical diagnostic approach to high-grade (G3) cases
.
Histopathology
.
2018
;
72
(
1
):
168
77
.
4.
Rindi
G
,
Klimstra
DS
,
Abedi-Ardekani
B
,
Asa
SL
,
Bosman
FT
,
Brambilla
E
, et al
.
A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal
.
Mod Pathol
.
2018
;
31
(
12
):
1770
86
.
5.
Woischke
C
,
Schaaf
CW
,
Yang
HM
,
Vieth
M
,
Veits
L
,
Geddert
H
, et al
.
In-depth mutational analyses of colorectal neuroendocrine carcinomas with adenoma or adenocarcinoma components
.
Mod Pathol
.
2017
;
30
(
1
):
95
103
.
6.
Yoshida
T
,
Kamimura
K
,
Hosaka
K
,
Doumori
K
,
Oka
H
,
Sato
A
, et al
.
Colorectal neuroendocrine carcinoma: a case report and review of the literature
.
World J Clin Cases
.
2019
;
7
(
14
):
1865
75
.
7.
La Rosa
S
,
Marando
A
,
Sessa
F
,
Capella
C
.
Mixed Adenoneuroendocrine Carcinomas (MANECs) of the Gastrointestinal Tract: An Update
.
Cancers (Basel)
.
2012
;
4
(
1
):
11
30
.
8.
Lin
J
,
Zhao
Y
,
Zhou
Y
,
Hao
H
,
He
Q
,
Tian
Y
, et al
.
Which staging system is more suitable for gastric neuroendocrine cancer and mixed adenoneuroendocrine carcinomas? A multicenter cohort study
.
Neuroendocrinology
.
2021
;
111
(
11
):
1130
40
.
9.
van der Veen
A
,
Seesing
MFJ
,
Wijnhoven
BPL
,
de Steur
WO
,
van Berge Henegouwen
MI
,
Rosman
C
, et al
.
Management of resectable esophageal and gastric (mixed adeno)neuroendocrine carcinoma: a nationwide cohort study
.
Eur J Surg Oncol
.
2018
;
44
(
12
):
1955
62
.
10.
La Rosa
S
,
Inzani
F
,
Vanoli
A
,
Klersy
C
,
Dainese
L
,
Rindi
G
, et al
.
Histologic characterization and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms
.
Hum Pathol
.
2011
;
42
(
10
):
1373
1384
.
11.
Jiang
M
,
Tan
Y
,
Li
X
,
Fu
J
,
Hu
H
,
Ye
X
, et al
.
Clinicopathological features and prognostic factors of colorectal neuroendocrine neoplasms
.
Gastroenterol Res Pract
.
2017
;
2017
:
4206172
.
12.
Mafficini
A
,
Scarpa
A
.
Genetics and epigenetics of gastroenteropancreatic neuroendocrine neoplasms
.
Endocr Rev
.
2019
;
40
(
2
):
506
36
.
13.
Shi
H
,
Zhang
Q
,
Han
C
,
Zhen
D
,
Lin
R
.
Variability of the Ki-67 proliferation index in gastroenteropancreatic neuroendocrine neoplasms-a single-center retrospective study
.
BMC Endocr Disord
.
2018
;
18
(
1
):
51
.
14.
Duan
X
,
Zhao
M
,
Yin
X
,
Mi
L
,
Shi
J
,
Li
N
, et al
.
Molecular typing and mutational characterization of rectal neuroendocrine neoplasms
.
Cancer Med
.
2023
;
12
(
15
):
16207
20
.
15.
Tang
JY
,
Gao
H-J
,
Shi
G-D
,
Guo
XK
,
Yu
WQ
,
Wang
HF
, et al
.
Development and validation of a nomogram prognostic model for patients with neuroendocrine tumors of the thymus
.
Thorac Cancer
.
2020
;
11
(
9
):
2457
64
.
16.
Li
X
,
Fan
Y
,
Tong
J
,
Lou
M
.
Risk factors, prognostic factors, and nomograms for distant metastases in patients with gastroenteropancreatic neuroendocrine tumors: a population-based study
.
Front Endocrinol
.
2024
;
15
:
1264952
.
17.
Zhang
BL
,
Lu
YX
,
Liang
WQ
,
Gao
YH
,
Xi
HQ
,
Wang
XX
, et al
.
Analysis of clinicopathological characteristics, therapeutic strategy and prognosis of 501 patients with gastric neuroendocrine neoplasms attending a single center
.
Zhonghua Wei Chang Wai Ke Za Zhi
.
2023
;
26
(
5
):
459
66
.
18.
Choi
NY
,
Kim
B-S
,
Oh
ST
,
Yook
JH
,
Kim
BS
.
Comparative outcomes in patients with small- and large-cell neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) of the stomach
.
Am Surg
.
2021
;
87
(
4
):
631
7
.
19.
Frizziero
M
,
Wang
X
,
Chakrabarty
B
,
Childs
A
,
Luong
TV
,
Walter
T
, et al
.
Retrospective study on mixed neuroendocrine non-neuroendocrine neoplasms from five European centres
.
World J Gastroenterol
.
2019
;
25
(
39
):
5991
6005
.
20.
Park
JY
,
Ryu
MH
,
Park
YS
,
Park
HJ
,
Ryoo
BY
,
Kim
MG
, et al
.
Prognostic significance of neuroendocrine components in gastric carcinomas
.
Eur J Cancer
.
2014
;
50
(
16
):
2802
9
.
21.
Shi
H
,
Qi
C
,
Meng
L
,
Yao
H
,
Jiang
C
,
Fan
M
, et al
.
Do neuroendocrine carcinomas and mixed neuroendocrine-non-neuroendocrine neoplasm of the gastrointestinal tract have the same prognosis? A SEER database analysis of 12,878 cases
.
Ther Adv Endocrinol Metab
.
2020
;
11
:
2042018820938304
.
22.
Ishida
S
,
Akita
M
,
Fujikura
K
,
Komatsu
M
,
Sawada
R
,
Matsumoto
H
, et al
.
Neuroendocrine carcinoma and mixed neuroendocrine‒non-neuroendocrine neoplasm of the stomach: a clinicopathological and exome sequencing study
.
Hum Pathol
.
2021
;
110
:
1
10
.
23.
Wu
R
, Gandhi
S
,
Tokumaru
Y
,
Asaoka
M
,
Oshi
M
,
Yan
L
, et al
.
Intratumoral PDGFB gene predominantly expressed in endothelial cells is associated with angiogenesis and lymphangiogenesis, but not with metastasis in breast cancer
.
Breast Cancer Res Treat
.
2022
;
195
(
1
):
17
31
.
24.
Zhu
L
,
Zhou
D
,
Chen
Y
,
Guo
T
,
Chen
W
,
Pan
X
.
Correlation analysis of the TP53 mutation with clinical characteristics in the prognosis of non-small cell lung cancer
.
Clin Med Insights Oncol
.
2023
;
17
:
11795549231184918
.
25.
Fareez
F
,
Wang
BH
,
Brain
I
,
Lu
JQ
.
Lymphomas in patients with neurofibromatosis type 1 (NF1): another malignancy in the NF1 syndrome
.
Pathology
.
2023
;
55
(
3
):
302
14
.
26.
Dai
Q
,
Zhang
J
,
Long
W
,
Haybaeck
J
,
Yang
Z
.
Genetic alterations of GI-NECs involving three main signaling pathways
.
Cancer Med
.
2023
;
12
(
7
):
8238
50
.
You do not currently have access to this content.